Botulinum toxin and the treatment of primary disorders of mood and affect

ABSTRACT

The invention provides methods for treating primary disorders of mood and affect, including depressive disorders, anxiety and sleep disorders and CNS disorders comprising the administration of a neurotoxin.

This application claims benefit to U.S. Provisional Application Ser. No.60/690,162, filed on Jun. 14, 2005; U.S. Provisional Application Ser.No. 60/693,771, filed on Jun. 27, 2005; U.S. Provisional ApplicationSer. No. 60/721,060, filed on Sep. 28, 2005; U.S. ProvisionalApplication Ser. No. 60/738,981, filed on Nov. 23, 2005, all of whichare hereby incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to the treatment of primary disorders ofmood and affect with a neurotoxin, including depressive, anxiety andsleep disorders as well as other CNS disorders.

BACKGROUND OF THE INVENTION

Depression is one of the most prevalent and pervasive forms of mentalillness that affects individuals across age and gender lines. (Gainottiet al. (2001) J. Neural Neurosurg. Psychiatr. 71: 258-261; Wong et al.(2001) Nature Rev. Neurosci. 2: 343-351; Nestler et al. (2002) Neuron34: 13-25). The lifetime risk of major depression is about 12% in menand about 25% in women, generally, (Kessler et al (1994) Arch. Gen.Psychiatry 51: 8). In addition, about 5 to 10% of all patients in theprimary care environment, present with major depression, whereas about 3to 5% of patients are diagnosed with dysthymia. (Barrett et al. (1988)Arch. Gen. Psychiatry 45: 1100). In an in-patient setting, however,between 10 and 14% of all patients are diagnosed with major depression.(Blackburn et al. (1997) Br. J Psychiatry 171: 328). Major depression isa particularly disabling and pernicious, in part, because it isrecurring. The rate of relapse for patients with major depression isabout 40% over a two-year period after a first episode. The occurrenceof relapse increases to about 75% within a five year period after thediagnosis of a second episode of major depression. (Solomon et al.(2000) Am. J Psychiatry 157: 229).

Depressive disorders are most commonly treated with three main classesof compounds: 1) monamine oxidase inhibitors; 2) heterocyclicantidepressants; and 3) selective serotonin reuptake inhibitors (SSRIs).The known and currently prescribed antidepressants are by numerous sideeffects. Monoamine oxidase inhibitors were the first class ofantidepressants used clinically. Monoamine oxidase inhibitors, includingisocarboxazid, phenelzine, and tranylcypromine, inhibit the metabolismof phenylethylamine and catabolism of dopamine, serotonin andnorepinephrine. As a consequence of numerous dietary restrictionsassociated with the use of monoamine oxidase inhibitors, extensive sideeffects, including hypertension, headache, myoclonic jerk, sleepdisruption, and gastrointestinal complications, monoamine oxidaseinhibitors are currently not used as a first-line antidepressant. Thetricyclic antidepressants, including, imipramine, desipramine,nortrypline, amitrypline, doxepin and protrypline, produce a variety ofanticholinergic side effects, drowsiness, orthostatic hypotension,cardiac arrhythmias and weight gain. Although generally milder than themonoamine oxidase inhibitors and the tricyclic antidepressants, SSRIsalso produce numerous side effects. For example, SSRIs, includingfluoxetine, paroxetine, fluvoxamine, sertraline, and citalopram, areassociated with gastrointestinal distress, jitteriness, agitation andsleep disruption.

In addition to the numerous side effects associated with traditionalantidepressant medications, these therapeutics are also characterized bymarginal efficacy. Several studies on the efficacy of antidepressanttherapy for major depression have concluded that the treatment of acutedisease or maintenance therapy is associated with a 50-60% responserate. (Schulberg et al. (1998) Arch. Gen. Psychiatry 55: 1121). Theaverage absolute response rate between antidepressants and placebo isabout 20-25%. (Williams et al. (2000) Ann. Intern. Med. 132: 743).Consequently, there is a current need for new antidepressant therapies.

In view of the sometimes severe adverse side effects and marginalefficacy of numerous antidepressant therapies, there is a great need forimproved pharmaceuticals that effectively treat depressive disorders andsleep disorders without producing the side effects associated withtreatments of depression and/or sleep disorders. The present inventionprovides compositions comprising botulinum toxin neurotoxin for thetreatment of depressive and/or sleep disorders as well as other CNSdisorders.

The effects of botulinum toxin-based pharmaceuticals for medicinalapplications has traditionally been though to act on the peripheralmotor and possibly sensory nerves. Such actions of these agents havebeen used to explain most of the beneficial effects for variousindications including movement disorders, pain syndromes, autonomicbased syndromes and spastic disorders. To date, clinical observationshave been made by the inventor which are indicative of the involvementof the central nervous system and cannot be explained by peripheraleffects. Effects on the central nervous system are observed even whenbotulinum toxin is administered to the scalp, facial or neck regions,including administration by any form of injection except intracranialinjection. Such observations include: improvement in photophobia withperi-ocular injections; improvement in sleep patterns and relief ofinsomnia; improvement of anxiety out of proportion to problems correctedby physical/muscular impairments; improvement in depression out ofproportion to problems created by physical/muscular impairment; andeffects on dysmenorrheal symptoms and potential effects on gonadotropinhormones or other pituitary hormones.

Additionally, botulinum toxin has been shown to have effects onneurotransmission within the central nervous system when the agent isdirectly injected into brain parenchyma. Alterations have includeddepression in electrode depolarization, depression in glutamate release,GABA staining, and cleavage of SNAP-25 in duration consistent withbotulinum toxin effect. Intraparenchymal brain injections have beenassociated with depression of seizure activity within the cerebralhemispheres when seizure provoking scarring is induced by causticchemical injections. Direct injection into the brain is not practicaland in fact unlikely to be conventionally practiced by a physicianskilled in the treatment of seizure disorders because of the possibilityand risk associated with induced hemorrhage, scarring, neuronal loss andplacement difficulty, infection (meningitis) and inconvenienceassociated with necessary delivery mechanisms. Direct injection into theCNS is highly impractical because of such complications associated withinvasive intracranial procedures. Described herein is a system fordelivery to the central nervous system (through methods ofadministration and injection that expressly do not include transcranial,intrathecal or intraspinal injection) of botulinum toxin-basedpharmaceuticals, allowing penetration into the central nervous systemwith enhanced convenience and safety, with fewer or mitigated adverseeffects associated with direct delivery.

The present inventors have surprisingly and unexpectedly discoveredcriteria for the selection of subjects for the treatment of painsyndromes with botulinum toxin. The present invention provides methodsfor identifying subjects with an increased responsiveness to thetreatment of pain with botulinum toxin. Specifically, the inventors havediscovered that atopic disease is associated with various painsyndromes, and the presence of atopic disease and relief of pain bytactile stimulation, geste antagoniste phenomenon, seem to havepredictive value in forecasting pain response to botulinum toxin.

The application of botulinum toxin for the treatment of myofacial paininitially included tension headaches, bruxism, temporal mandibular jointsyndrome, lower-back pain, and post-surgical pain after cervicalsurgical incisions for the treatment of acoustic neuroma (posteriorfossa brain tumor). Application of botulinum toxin for the treatment ofmigraine headaches became popular after the coincident observation thatmigraine headaches were relieved after the of botulinum toxin to effacefacial wrinkles on the forehead.

Multiple case reports suggest that botulinum toxin is effective for thetreatment of tension and migraine headaches, as well as forms ofmyofacial pain syndrome. Despite this suggestion, controlled trialsusing small numbers of patients in the study groups, have failed todemonstrate the efficacy of botulinum toxin for the treatment ofmyofascial and other forms of pain. (Wheeler et al. (1998) A randomized,double-blind, prospective pilot study of botulinum toxin injection forrefractory, unilateral, cervicothoracic, paraspinal, myofascial painsyndrome. Spine 23(15): 1662-6). The ineffectiveness of botulinum toxinto treat a variety of pain syndromes, in controlled trial, has beenattributed to small sample size and relatively low statistical power.The need for larger numbers of patients and further multi-centerinvestigations have been deemed necessary to provide stronger evidenceof effectiveness.

In view of case reports suggesting that botulinum toxin is indeedeffective for the treatment of migraine-headache-pain syndromes, effortswere made to conduct larger-scale studies. In an initial multi-centercontrolled study sponsored by the Allergan Pharmaceutical Company, oneof the largest suppliers of botulinum toxin A (BOTOX-TM), efficacy ofbotulinum toxin to prevent the repetitive occurrence of common migraineheadaches (as defined by the International Headache Classification-1988)was suggested. The statistical significance of these results, however,was uncertain, inconsistent between treatment groups, and exhibitedunexplained inverted dose response curves. (Silberstein et al. (2000)Botulinum toxin type A as a migraine preventive treatment. Headache40(6): 445-50).

Migraine, tension headaches, myofascial pain of the head, and chronicatypical facial headaches are representative of primary-headachedisorders (headaches not associated with structural pathology within thehead or not secondary to another disease process). Treatment of theseconditions is associated with very high placebo response rates (up to35%), requiring large numbers of patients to detect significantdifferences in clinical trials between study and control groups.Utilization of selection criteria (study-induction criteria) thatidentify a more responsive patient population increases the responserate for subjects within treatment groups of controlled studies, which,in turn, allows a smaller test sample to establish therapeutic efficacyin controlled trials. More importantly, selection criteria (diagnosticcriteria) are the basis for accurate and effective medical therapy forany condition. Parameters which identify patients more likely to respondto a given treatment allow: 1) prioritization among therapies whenmultiple therapeutic options exist; 2) avoidance of therapy unlikely tobe successful; and 3) facilitation of informed consent from patientsconsidering risks and benefit ratios. Effective selection criteriaassist researchers to further understand mechanisms of action based onclinical evidence.

The present invention provides methods of selecting patients sufferingfrom various pain syndromes, including, but not limited to, myofascialpain, muscle tension headache, and chronic post operative woundsyndromes, based on retrospective and prospective analysis in theapplication of botulinum toxin for the treatment of pain syndromesinvolving the head and neck.

SUMMARY OF THE INVENTION

The present invention provides methods of treating depressive, anxietyand sleep disorders comprising the administration of pharmaceuticalcompositions comprising neurotoxins.

The present invention provides methods for treating depressioncomprising the steps of: a) identifying a subject with a depressivedisorder or identifying a subject with one or more symptoms of adepressive disorder; and b) administering an effective amount of acomposition comprising a botulinum toxin and a pharmaceuticallyacceptable carrier to said subject.

The present invention also provides methods of treating anxietycomprising the steps of: a) identifying a subject with an anxietydisorder or identifying a subject with at least one symptom of ananxiety disorder; and b) administering an effective amount of acomposition comprising a botulinum toxin and a pharmaceuticallyacceptable carrier to said subject.

The present invention also provides methods of treating sleep disorderscomprising the steps of: a) identifying a subject with a sleep disorderor identifying a subject exhibiting at least one symptom of a sleepdisorder; and b) administering an effective amount of a compositioncomprising a botulinum toxin and a pharmaceutically acceptable carrierto said subject.

The present invention also provides methods of treating circadian rhythmdisorders comprising the steps of: a) identifying a subject with acircadian rhythm disorder; and b) administering an effective amount of acomposition comprising a botulinum toxin and a pharmaceuticallyacceptable carrier to said subject.

The present invention also provides methods of delivering botulinumtoxin across a blood-brain barrier comprising the steps of: a)identifying a subject with at least one neuropsychiatric disorder; andb) administering a composition comprising a neurotoxin and apharmaceutically acceptable carrier to said subject in an amountsufficient to deliver said neurotoxin across the blood-brain barrier.

The present invention also provides methods of delivering botulinumtoxin across a blood-brain barrier comprising the steps of: a)identifying a subject with at least one neuropsychiatric disorder; andb) administering a composition comprising a neurotoxin and apharmaceutically acceptable carrier to said subject in an amountsufficient to deliver said neurotoxin across the blood-brain barrier,wherein said administration of said injection of neurotoxin blocks atleast one neurotransmitter. In a preferred embodiment, theneurotransmitter is acetylcholine.

The present invention also provides methods of treating an anxietydisorder comprising the steps of: a) identifying a subject with at leastone anxiety disorder or identifying a subject with one or more symptomsof an anxiety disorder; and b) administering to said subject acomposition comprising a neurotoxin and a pharmaceutically acceptablecarrier said composition is delivered across the blood-brain barrier inan amount sufficient to decrease cholinergic neuron transmission.

The present invention also provides methods of treating a sleep disordercomprising the steps of: a) identifying a subject with at least onesleep disorder or identifying a subject with one or more symptoms of asleep disorder; and b) administering to said subject a compositioncomprising a neurotoxin and a pharmaceutically acceptable carrier saidcomposition is delivered across the blood-brain barrier in an amountsufficient to decrease cholinergic neuron transmission. In a preferredembodiment, the composition decreases choline acetyltransferaseactivity. In another preferred embodiment, the composition decreases thesynthesis of acetylcholine. In another preferred embodiment, the sleepdisorder is insomnia. In another preferred embodiment, the sleepdisorder is narcolepsy, restless leg syndrome or sleep apnea.

The present invention also provides methods of treating a circadianrhythm disorder comprising the steps of: a) identifying a subject withat least one circadian rhythm disorder or identifying a subject with oneor more symptoms of a circadian rhythm disorder; and b) administering tosaid subject a composition comprising a neurotoxin arid apharmaceutically acceptable carrier said composition is delivered acrossthe blood-brain barrier in an amount sufficient to decrease cholinergicneuron transmission. In a preferred embodiment, the compositiondecreases choline acetyltransferase activity. In another preferredembodiment, the composition decreases the synthesis of acetylcholine.

The present invention also provides methods of treating a depressivedisorder comprising the steps of: a) identifying a subject with at leastone depressive disorder or identifying a subject with one or moresymptoms of a depressive disorder; and b) administering to said subjecta composition comprising a neurotoxin and a pharmaceutically acceptablecarrier said composition is delivered across the blood-brain barrier inan amount sufficient to decrease cholinergic neuron transmission. In apreferred embodiment, the composition decreases cholineacetyltransferase activity. In another preferred embodiment, thecomposition decreases the synthesis of acetylcholine.

The present invention provides methods of selecting a subject for thetreatment of pain with botulinum toxin, comprising the step ofidentifying a subject suffering from a pain syndrome and a conditionselected from the group consisting of a depressive disorder, an anxietydisorder and a sleep disorder, wherein the identification of a subjectwith a pain syndrome and a condition selected from the group consistingof a depressive disorder, an anxiety disorder and a sleep disorder ispredictive of increased responsiveness to the treatment of pain withbotulinum toxin. In a preferred embodiment, the pain syndrome is any oneor a combination of the pain syndromes selected from the groupconsisting of; myofacial pain; migraine headache; post operative wouldpain; sinusitis-related headaches; muscle tension headaches;post-traumatic headaches; cluster headaches; temporal mandibular jointsyndrome; fibromyalgia; atypical facial pain; post incisional woundpain; cervical radiculopathy; and whiplash.

In another embodiment of the present invention, subjects suffering froma condition selected from the group consisting of a depressive disorder,an anxiety disorder and a sleep disorder were identified by determiningthat a subject has a medical history of a depressive disorder, ananxiety disorder, or a sleep disorder, respectively.

The present invention also provides methods of identifying a subjectwith increased responsiveness to treating a pain disorder with botulinumtoxin, comprising the step of screening a population of subjects toidentify those subjects that suffer from a pain disorder and a conditionselected from the group consisting of a depressive disorder, an anxietydisorder and a sleep disorder, wherein the identification of a subjectwith a pain syndrome and a condition selected from the group consistingof a depressive disorder, an anxiety disorder and a sleep disorder ispredictive of increased responsiveness to the treatment of pain withbotulinum toxin. In a preferred embodiment, the pain syndrome is any oneor a combination of the pain syndromes selected from the groupconsisting of: myofacial pain; migraine headache; post operative wouldpain; sinusitis-related headaches; muscle tension headaches;post-traumatic headaches; cluster headaches; temporal mandibular jointsyndrome; fibromyalgia; atypical facial pain; post incisional woundpain; cervical radiculopathy; and whiplash.

The present invention provides a method that comprises the steps ofidentifying or diagnosing a pain syndrome; diagnosing or eliciting ahistory of a condition selected from the group consisting of adepressive disorder, an anxiety disorder and a sleep disorder; andclassifying the identified pain syndrome as one with increasedresponsiveness to treatment with botulinum toxin. In one embodiment, apain syndrome is identified according to the International HeadacheClassification System (The International Headache Society (I.H.S.)).

The present invention provides a method of selecting patients for thetreatment of human headache disorders with a botulinum toxin basedpharmaceutical, comprising diagnosing headache type occurring in apatient suffering from a depressive disorder, an anxiety disorder,obsessive compulsive behavioral traits, or a sleep disorder andadministering a therapeutically effective amount of botulinum toxin. Inone embodiment the headache disorder is migraine, tension headache,combined tension and migraine headache, myofascial headache, sinusheadache, headache associated with temporal mandibular joint syndrome,headache associated with fibromyalgia, or headache associated withneuralgia.

The present invention also provides a method of selecting patients forthe treatment of human facial pain disorders with a botulinum toxinbased pharmaceutical, comprising diagnosing a facial pain disorderoccurring in a patient suffering from a depressive disorder, an anxietydisorder, obsessive compulsive behavioral traits, or a sleep disorderand administering a therapeutically effective amount of botulinum toxin.In one embodiment, the facial pain disorder is trigeminal neuralgia, thefacial pain disorder is associated with bruxism, or the facial paindisorder is post operative chronic surgical wound pain.

The compositions of the present invention comprise botulinum toxin and apharmaceutically acceptable carrier. In a preferred embodiment, thebotulinum toxin is immunotype A, B, C, D, E, F, or G. In a morepreferred embodiment, the botulinum toxin is botulinum toxin type A fromHall strain Clostridium botulinum.

The methods of the present invention may preferably be practiced byadministering the botulinum toxin compositions by injection, includingtranscutaneous, percutaneous, subcutaneous, intraperitoneal,transdermal, intramuscular and intraosseous, but expressly notintracranial, transcranial, intrathecal or intraspinal injection oradministration. In one embodiment, there are at least two injectionsites. In another embodiment, the injections are multifocal. Thebotulinum toxin may be preferably administered to the forehead, scalp orneck or other locations such as the periocular region and other areas ofthe face that enhance maximize venous drainage from the site ofadministration to the central nervous system (CNS). In anotherembodiment, the botulinum toxin may be administered to the soft tissuesoutside the neurocranium. In another embodiment, the botulinum toxin maybe administered in locations that maximize uptake by the portalhypophyseal drainage.

Examples of compounds and formulations which can be used in the presentinvention include botulinum toxin stabilized with a protein such asserum albumin or hyaluronidase. In a preferred embodiment the serumalbumin or hyaluronidase is recombinant. In another embodiment, theserum albumin is present at a concentration of greater than 500 μg/100LD₅₀ units botulinum toxin. The botulinum toxin pharmaceutical may befurther stabilized with a simple stabilizing sugar or polysaccharide(e.g. sucrose, lactose or trehalose). The botulinum toxin is preferablya monocomponent neurotoxin of a molecular weight of 150,000 daltons thatis free of complex botulinum toxin proteins. The compositions disclosedherein may also comprise a polyethylene glycol polymer; a vegetablefat-based nanoemulsion; and any nanoemulsion using one or moremonounsaturated or polyunsaturated oils. In a preferred embodiment, thebotulinum toxin compositions used in the methods of the presentinvention are formulated to enhance penetration of the botulinum toxininto and through the skin.

Recent advances in pharmaceutical technology have focused on enhanceddelivery systems such as transdermal or transcutaneous delivery systems.Such systems are thought to be more convenient and associated with lesspain. The problems associated with such systems include poor penetrationof materials through the epidermis and dermis. Hyaluronidase offersimproved penetration.

A pharmaceutical composition comprising botulinum neurotoxin,hyaluronidase, and sugars (both simple and oligosaccharides) is suitablefor the methods of the present invention. The botulinum toxinpharmaceutical formulations suitable for use in for the methods of thepresent invention are preferably devoid of any human blood orrecombinant blood products and will be either stabilized in flash orfreeze dried form. The pH is preferably between pH 3.0 to 7.4 and thepreparation may be used as an injection, transdermal or topical agent.The botulinum toxin pharmaceutical formulations suitable for use in forthe methods of the present invention may be administered by injection,needleless delivery systems and methods requiring disruption techniquessuch as electroporation, sonication, and high pressure air gas flowinjection or in the form of a micro-needle. Micro-needles are generallyfrom 150 to 600 microns. Furthermore, the botulinum toxin pharmaceuticalformulations suitable for use in for the methods of the presentinvention may further comprise polycationic proteins.

Currently, hyaluronidase is available at a number of specificactivities. For example, sheep based materials can have a specificactivity of 1,500 U per mg or 1.5 U per mcg. Typically, 75-300 U areused for injection, such as conducted with peri-bulbar anesthesia forintra-ocular surgery. This would correspond to about 100-450 mg in massof enzymatic protein, enough to act as a stabilizing excipient.

Prior studies have show that a protein excipient, such as human serumalbumin, can stabilize the botulinum toxin. Test studies conducteddemonstrate that hyaluronidase also stabilizes the botulinum toxin atthe same levels observed for the human serum albumin.

The compositions disclosed herein may be such that the doses areformulated into a concentration suitable for administration as an eyedrop to facilitate transconjunctival penetration for the treatment ofocular surface diseases. The compositions disclosed herein may be suchthat the LD₅₀ units range from 1.25U-3,000 units of botulinum toxin typeA. The compositions disclosed herein may be such that the LD₅₀ unitsrange from 1.25 -20,000 U of botulinum type B. The compositionsdisclosed herein may be such that the formulation is delivered into thenose or oral cavity as an aerosol to facilitate intracranial delivery ofa botulinum toxin based pharmaceutical. The compositions disclosedherein may be such that the formulation is delivered into the ear canalas an aerosol to facilitate intracranial delivery of a botulinum basedpharmaceutical

The present invention provides methods for delivering a botulinum toxinbased pharmaceutical to the central nervous system of a subject by anyinjection or topical application method, except intracranial,transcranial, intrathecal or intraspinal injection, in a therapeuticallyeffective amount sufficient to decrease at least one central nervoussystem neurotransmitter when compared to an untreated subject. In apreferred embodiment, the at least one central nervous systemneurotransmitter is glutamate, norepinephrine, or acetyl-choline. In amore preferred embodiment, the at least one central nervous systemneurotransmitter is glutamate. In another embodiment, the methods of thepresent invention decrease at least one central nervous systemneurotransmitter when compared to an untreated subject sufficiently toreduce at least one symptom of insomnia, a sleep disorder, an anxietydisorder, a depressive disorder, dysmenorrhea, an appetite or eatingdisorder, or a seizure disorder. In a preferred embodiment the seizuredisorder is generalized, focal motor, or partial complex.

Glutamate is a neurotransmitter that exhibits endogenous neurotoxicactivity that is observed in a number of neurodegenerative diseases anddisorders, vascular accidents such as stroke and in seizure disorders.For example, subjects with mild to moderate dementia and probableAlzheimer's Disease have been shown to exhibit elevated levels ofglutamate in the central nervous system. Elevated glutamate in thecentral nervous system is reflective of increased glutamatergic activityin the early stages of Alzheimer's Disease. The progressive neuronalloss observed in Alzheimer's Disease and other neurodegenerativedisorders and diseases correlate with elevated glutamate and theincreased excitotoxicity associated with elevated levels of thisneurotransmitter.

The present invention provides methods for reducing glutamate levels inthe central nervous system, the brain or portions of the braincomprising the step of administering a botulinum toxin pharmaceutical toa subject, by any injection or topical application method, exceptintracranial, transcranial, intrathecal or intraspinal injection, in anamount sufficient to reduce glutamate levels in the central nervoussystem, the brain or portions of the brain compared to an untreatedsubject.

The present invention provides methods for neuroprotection comprisingthe step of administering a botulinum toxin pharmaceutical to a subject,by any injection or topical application method, except intracranial,transcranial, intrathecal or intraspinal injection, in an amountsufficient to reduce neuronal loss in the central nervous system, thebrain or portions of the brain compared to an untreated subject.

The present invention also provides methods for delivering a botulinumtoxin based pharmaceutical to the central nervous system of a subject byinjection into the nasal sinuses in a therapeutically effective amountsufficient to decrease at least one central nervous systemneurotransmitter when compared to an untreated subject. In a preferredembodiment, the at least one central nervous system neurotransmitter isglutamate, norepinephrine, or acetyl-choline. In a more preferredembodiment, the at least one central nervous system neurotransmitter isglutamate. In another embodiment, the methods of the present inventiondecrease at least one central nervous system neurotransmitter whencompared to an untreated subject sufficiently to reduce at least onesymptom of insomnia, a sleep disorder, an anxiety disorder, a depressivedisorder, dysmenorrhea, or a seizure disorder. In a preferred embodimentthe seizure disorder is generalized, focal motor, or partial complex.

The present invention also provides methods for delivering a botulinumtoxin based pharmaceutical to the central nervous system of a subject byany injection or topical application method, except intracranial,transcranial, intrathecal or intraspinal injection, in a therapeuticallyeffective amount sufficient to decrease at least one central nervoussystem neurotransmitter when compared to an untreated subject. In apreferred embodiment, the at least one central nervous systemneurotransmitter is glutamate, nor-epinephrine, or acetyl-choline. In amore preferred embodiment, the at least one central nervous systemneurotransmitter is glutamate. In another embodiment, the methods of thepresent invention decrease at least one central nervous systemneurotransmitter when compared to an untreated subject sufficiently toreduce an agitated behavior associated with mental retardation,schizophrenia, Huntington's Chorea or Alzheimer's Disease.

The present invention also provides methods for delivering a botulinumtoxin based pharmaceutical to the central nervous system of a subject byany injection or topical application method, except intracranial,transcranial, intrathecal or intraspinal injection, in a therapeuticallyeffective amount sufficient to decrease at least one central nervoussystem neurotransmitter when compared to an untreated subject. In apreferred embodiment, the at least one central nervous systemneurotransmitter is glutamate, nor-epinephrine, or acetyl-choline. In amore preferred embodiment, the at least one central nervous systemneurotransmitter is glutamate. In another embodiment, the methods of thepresent invention decrease at least one central nervous systemneurotransmitter when compared to an untreated subject sufficiently toreduce at least one symptom of a neurodegenerative disease associatedwith inflammation.

The present invention also provides for the use of botulinum toxin or abotulinum toxin composition of the present invention in the productionof a medicament for the treatment of any one of the disorders, diseasesor conditions disclosed herein, including depressive disorders, anxietydisorders, sleep disorders, circadian rhythm disorders, neuropsychiatricdisorders, Alzheimer's Disease and the like, and for the treatment ofpain, such as various headache pain, associated with a pain syndrome.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the decreased glutamate receptor activity in theneostriatum of a botulinum-toxin-treated mouse as compared to anuntreated mouse.

DETAILED DESCRIPTION OF THE INVENTION A. Definitions

As used herein, “administration” of a composition means any route ofadministration, including but not limited to oral, nasal,transcutaneous, percutaneous, subcutaneous, intraperitoneal,transdermal, intramuscular and intraosseous, but expressly excludesadministered by any method, except intracranial, transcranial,intrathecal or intraspinal injection.

As used herein, “Botulinum toxin” means a protein toxin and itscomplexes isolated from strains of Clostridium botulinum, includingvarious immunotypes such as A, B, C1, C2, C3, D, E, F and G.

As used herein, “depressive disorder” means major depression, dysthymia,and atypical depression or depression not otherwise specified.

As used herein, “an effective amount” is an amount sufficient to reduceone or more symptoms associated with a depressive, anxiety or sleepdisorder or any of the disorders described herein.

As used herein, the term “pharmaceutically acceptable carrier” means achemical composition with which the active ingredient may be combinedand which, following the combination, can be used to administer theactive ingredient to a subject. “Pharmaceutically acceptable carrier”also includes, but is not limited to, one or more of the following:excipients; surface active agents; dispersing agents; inert diluents;granulating and disintegrating agents; binding agents; lubricatingagents; sweetening agents; flavoring agents; coloring agents;preservatives; physiologically degradable compositions such as gelatin;aqueous vehicles and solvents; oily vehicles and solvents; suspendingagents; dispersing or wetting agents; emulsifying agents, demulcents;buffers; salts; thickening agents; fillers; emulsifying agents;antioxidants; antibiotics; antifungal agents; stabilizing agents; andpharmaceutically acceptable polymeric or hydrophobic materials. Other“additional ingredients” which may be included in the pharmaceuticalcompositions of the invention are known in the art and described, forexample in Genaro, ed., 1985, Remington's Pharmaceutical Sciences, MackPublishing Co., Easton, Pa., which is incorporated herein by reference.

As used herein, “increased responsiveness” refers to an increase in theratio of subjects responsive to pain treatment with botulinum toxin tototal subjects (responsive and unresponsive to botulinum toxin).

As used herein, “response ratio” refers to the ratio of subjectsresponsive to pain treatment with botulinum toxin to total subjects(responsive and unresponsive to botulinum toxin).

As used herein, the term “screening a population” means a retrospectivereview and analysis of the medical history of a subject or anidentification of a specific contemporaneous diagnosis.

The formulations of the pharmaceutical compositions described herein maybe prepared by any method known or hereafter developed in the art ofpharmacology. In general, such preparatory methods include the step ofbringing the active ingredient into association with a carrier or one ormore other accessory ingredients, and then, if necessary or desirable,shaping or packaging the product into a desired single- or multi-doseunit.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for ethical administration to humans, it will be understood bythe skilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and perform such modification with merely ordinary, if any,experimentation. Subjects to which administration of the pharmaceuticalcompositions of the invention is contemplated include, but are notlimited to, humans and other primates, and other mammals.

The relative amounts of the active ingredient, the pharmaceuticallyacceptable carrier, and any additional ingredients in a pharmaceuticalcomposition of the invention will vary, depending upon the identity,size, and condition of the subject treated and further depending uponthe route by which the composition is to be administered. By way ofexample, the composition may comprise between 0.1% and 100% (w/w) activeingredient. In addition to the active ingredient, a pharmaceuticalcomposition of the invention may further comprise one or more additionalpharmaceutically active agents. Particularly contemplated additionalagents include anti-emetics and scavengers such as cyanide and cyanatescavengers. Controlled- or sustained-release formulations of apharmaceutical composition of the invention may be made usingconventional technology.

As used herein, the term “physiologically acceptable” ester or saltmeans an ester or salt form of the active ingredient which is compatiblewith any other ingredients of the pharmaceutical composition, which isnot deleterious to the subject to which the composition is to beadministered.

B. Depressive Disorders

Depressive disorders encompass the diagnoses of major depression,dysthymia, and atypical depression or depression not otherwise specified(“minor depression”). The different subgroups of depressive disordersare categorized and defined by the Diagnostic and Statistical Manual ofMental Disorders, Fourth Edition (DSM-IV). (American PsychiatricAssociation. Diagnostic and Statistical Manual of Mental Disorders,4^(th) Ed., Primary Care Version (DSM-IV-PC). American PsychiatricAssociation Press, Washington, D.C. 1995). According to the DSM-IV, adiagnosis of “major depression” requires that a patient present with atleast five of the following nine symptoms during the diagnosticperiod: 1) depressed mood most of the day (most acute in the morning);2) markedly diminished interest or pleasure in nearly all activities(anhedonia); 3) significant weight loss or gain; 4) insomnia orhypersomnia; 5) psychomotor agitation or retardation; 6) fatigue orenergy loss; 7) feelings of guilt and worthlessness; 8) impairedconcentration and indecisiveness; and 9) recurring thoughts of death orsuicide. To support a diagnosis of major depression, a depressed mood orloss of interest (anhedonia) must be one of the five observed symptoms.In contrast, a diagnosis of “atypical depression” or “depression nototherwise specified” (also referred to as “minor depression”), the mostcommon form of depression, requires between 2 and 4 depressive symptomsthat are present daily or for most of the day for at least a two weekperiod. Dysthymia is a chronic, low intensity mood disordercharacterized by anhedonia, low self esteem and low energy that persistsfor more than two years, consecutively. Seasonal affective disorder isconsidered to be a form of major depression characterized by seasonalvariation.

Depressive disorders do not include normal emotional reactions, a normalgrief reaction or reactions secondary to an organic cause such as aphysical illness or drug exposure. As used herein, depressive disordersrefer to primary disorders of mood and sleep patterns and not secondaryor reaction disorders. Such reactionary disorders occur secondarily toother medical disorders such as hyperhydrosis, cervical dystonia,migraine headache, tension headaches, various pain syndromes, jawspasms, blepharospasm, strabismus, inflammatory local and systemicdiseases, post operative pain syndromes, hemifacial spasms, cancer,myocardial infarction, stroke, degenerative neurological diseases, orany other physical ailment causing an emotional reaction.

C. Anxiety

Anxiety is a group of disorders characterized by a number of both mentaland physical symptoms, with no apparent explanation. Apprehension, fearof losing control, fear of going “crazy”, fear of pending death,impending danger, or uneasiness are among the most common mentalsymptoms. Common physical symptoms include dizziness, lightheadedness,chest pain, abdominal pain, nausea, increased hear rates or diarrhea.Chronic anxiety, also referred to as Generalized Anxiety Disorder,manifests as persistent worries, fears, and negative thoughts lasting aminimum of six months. Chronic anxiety often results in excessive worryover daily activities, headaches and nausea. Sleep disorders or earlyawakening, depression, tension, muscle aches and fatigue can allaccompany chronic anxiety.

Acute anxiety, or Panic Disorder, comes on as a sudden attack or fearaccompanied by symptoms that may resemble a heart attack, such aspalpitations, chest pain and dizziness. Shortness of breath, stomachupset, chills, cold sweats, hot flashes, or irrational fears of deathcan combine with these symptoms to create a terrifying experience forthe individual experiencing them. Excessive levels of nor epinephrineare seen to increase the rates of breathing and pulse in panic attacksufferers. Post-traumatic Stress Disorder is also classed as an anxietydisorder, and can be triggered by anyone experiencing or witnessing adeeply traumatic event. Some symptoms of Post-Traumatic Stress Disordercan be anger, depression, emotional numbness, flashbacks, nightmares anda tendency to startle easily.

Phobias, or irrational fears, and Obsessive Compulsive Disorder, atendency towards repetitive or uncontrollable behavior, are also classedwith anxiety disorders. These may co-exist together, as many individualswith obsessive compulsive disorder have phobias of germs or lack ofcleanliness and may was their hands or bathe excessively.

Anxiety disorders do not include normal emotional reactions, a normalreaction to stress or reactions secondary to an organic cause such as aphysical illness or drug exposure.

D. Sleep Disorders

Circadian rhythm describes the approximately 24-hour cycles that aregenerated by an organism. Most physiological systems demonstratecircadian variations. The systems with the most prominent variations arethe sleep-wake cycle, thermoregulation, and the endocrine system.Circadian rhythm disturbances can be categorized into two main groups:transient disorders (e.g., jet lag, altered sleep schedule due to work,social responsibilities, illness) and chronic disorders. The most commonchronic disorders are delayed sleep-phase syndrome (DSPS), advancedsleep-phase syndrome (ASPS), and irregular sleep-wake cycle. Katzenberget al. have suggested a genetic correlation (i.e., clock polymorphisms)to circadian rhythm patterns. DSPS is characterized by a persistentinability (more than 6 mo) to fall asleep and awaken at sociallyaccepted times. Once asleep, these patients are able to maintain theirsleep and have normal total sleep times. (In contrast, patients withinsomnia have a lower than normal total sleep time, due to difficultiesin initiating or maintaining sleep.) ASPS is characterized by persistentearly evening sleep onset (between 6:00 and 9:00 pm) with an earlymorning wake-up time, generally between 3:00 and 5:00 am. ASPS occursmuch less frequently than DSPS and is seen most commonly in the elderlyand in individuals who are depressed.

The neural basis of the circadian rhythm, the suprachiasmatic nuclei(SCN), is located in the anterior ventral hypothalamus and has beenidentified as the substrate that generates circadian activity. Lesionsof the SCN produce loss of circadian rhythmicity of the sleep-wakecycle, the activity-rest cycle, skin temperature, and corticosteroidsecretion. Other pacemakers exist that are not located in the SCN. Forinstance, core body temperature rhythm persists in spite of bilateralablation of SCN. Furthermore, free-running studies have providedevidence for multiple circadian oscillators. Under free-runningconditions, circadian rhythm may split into independent components.

The SCN are the site of the master circadian clock in mammals. The SCNclock is mainly entrained by the light-dark cycle. Light information isconveyed from the retina to the SCN through direct, retinohypothalamicfibers. The SCN also receive other projections, like cholinergic fibersfrom basal forebrain. Cholinergic afferents and transmission have beenshown to be involved in regulation of light-induced circadian rhythms.(Erhardt et al. 2004 The Neuroanantomy of the Circadian Rhythm.).

In the United States, DSPS is common. Approximately 7-10% of patientswho complain of insomnia are diagnosed with a circadian rhythm disorder,most often DSPS. The prevalence of DSPS is probably higher than thatbecause the total sleep time is typically normal in patients with DSPSand because patients with DSPS adjust their lifestyle to accommodatetheir sleep schedule and do not seek medical treatment. In adolescence,the prevalence is approximately 7%. In contrast, true ASPS probably isquite rare. An age-related phase advance, however, is common in theelderly, who tend to go to sleep early and get up early.

The diagnosis of circadian rhythm disorders is based primarily on athorough social, physical and neurological history. Differentiation oftransient disorders from chronic disorders and primary disorders fromsecondary disorders influences the direction of evaluation and treatmentplans. As with all medical and psychiatric histories, the nature of thecomplaint is the first order of business. In cases of sleeplessness,distinguishing individuals with difficulty initiating sleep from thosewith difficulty maintaining sleep, those with significant daytimeimpairment, and those complaining of nonrestorative sleep is important.

Disorders associated with various sleep disorders include narcolepsy,cataplexy, restless-leg syndrome, and sleep apnea. Anxiety disorders donot include normal emotional reactions, a normal reaction to stress orreactions secondary to an organic cause such as a physical illness ordrug exposure.

E. CNS Disorders

The present invention is also directed to methods of using botulinumtoxin based pharmaceuticals injected transcutaneously or by any of theroutes of administration disclosed herein, to induce a central nervoussystem depressive effect for the treatment of various CNS disorders. Theinventor has found that botulinum toxin exerts a CNS depressive effectin rats injected transcutaneously in the scalp. The injections are notintracranial or directly into the brain, but may include or specificallyexclude intrathecal and intraspinal injection or administration. It ishypothesized that transcutaneous administration of botulinum toxinpenetrates the blood/brain barrier. The present invention providesmethods for using the botulinum toxin based pharmaceuticals disclosedherein for the treatment of seizures, anxiety, agitation, mania, bipolardisorders, generalized seizures, mental retardation, delirium,hyperactivity syndrome, attention deficit disorder (ADD), dementia,Huntington's disease, Alzheimer's disease, Parkinson's disease,psychosis, schizophrenia, insomnia and other CNS disorders.

In certain embodiments, the botulinum toxin based pharmaceuticalsdisclosed herein are used at various dosage levels to induce ageneralized atrophic effect in the CNS. This effect is useful in thetreatment of various CNS disorders. The inventor has found that ratsinjected with high doses of botulinum toxin (i.e. doses at or near theLD₅₀) exhibit expanded or enlarged lateral ventricles in their brains.Controls show no such effects while treated animals show a markedeffect. Generalized brain atrophy is indicative of biological activityat the level of neurotransmitters that is induced by transcutaneousadministration of botulinum toxin. The evidence is consistent with asuppressive effect in the hypothalamus in the treated animals. Thiscould cause direct effects on the release of hormones such as thyroidreleasing factors, gonadotropin releasing factor, etc.

All books, articles, patents or other publications and references arehereby incorporated by reference in their entireties. Reference to anycompound herein includes the racemate as well as the single enantiomers.

EXAMPLES

The following Examples serve to further illustrate the present inventionand are not to be construed as limiting its scope in any way.

Example 1

A 78-year-old male who noted sleep disturbances and anxiety wasinitially diagnosed with blepharospasm. Botulinum toxin was administeredby injection, and the subject noted improved sleep and reduced anxiety.

Example 2

A 44-year-old bus driver was diagnosed with hemifacial spasm andreported symptoms of anxiety. Botulinum toxin was administered byinjection. The subject noted a better ability to cope with work-relatedstresses and cope with difficult situations with less stress.

Example 3

A 72-year-old consultant diagnosed with hemifacial spasm who reportedsleep disturbances and anxiety was treated with botulinum toxin that wasadministered by injection. The subject reported improved sleep andreduced anxiety and less agitation.

Example 4

A 45-year-old woman was treated for cosmetic indications with botulinumtoxin. The initial diagnosis was cosmetic rhytides. The subject notedfewer symptoms of depression and less anxiety for a period of twomonths.

Example 5

A 44-year-old woman diagnosed with severe tension headaches and sleepdisturbances was treated with botulinum toxin by injection. The subjectnoted improved sleep patterns and fewer headaches up to two months aftertreatment.

Example 6

A 73-year-old male with essential blepharospasm reported sleepdisturbances and anxiety characterized as “nervous tension.” Botulinumtoxin was administered by injection. The subject noted less anxiety andimproved sleep after the injections. The reduced symptoms lasted two tothree months and ultimately recurred.

Example 7

A 43-year-old person with myofacial pain and sleep problems was treatedwith botulinum toxin by injection. The subject noted better sleeppatterns after injections that lasted three months.

Example 8

A 42-year-old person was diagnosed with myofacial pain, tensionheadaches and depression and treated with botulinum toxin administeredby injection. The subject noted some improvement in sleep pattern afterthe toxin injections.

Example 9

The subject is a 54-year-old person diagnosed with essentialblepharospasm and depression. Botulinum toxin was introduced byinjection. The subject noted fewer symptoms of depression after thebotulinum toxin injections.

Example 10

The subject is a 57-year-old physician diagnosed with essentialblepharospasm. Botulinum toxin was introduced by injection. The subjectnoted a feeling of euphoria, well being and improved mood after thebotulinum toxin injections.

Example 11

A 47 year old woman with a history of cervicogenic headache and frequentproblems of insomnia. The insomnia was characterized by difficultyinitiating sleep, intermittent awakening, early-morning awakening, andinability to maintain sleep. Injections were given in the regionsgenerally used to treat spasmodic torticollis as well as in multiplelocations along the hairline, both anterior and posterior. Doses rangedbetween 5-20 units per subcutaneous injection site with a total dose of100 U. Within 3-5 days, improvement in the insomnia occurred and lastedbetween 10-14 weeks. Improvement in each component of her sleep disorderoccurred. Recurrence of the sleep disorder occurred after the 10-14 weekperiod.

Example 12

A 52 year old woman received botulinum injections for the effacement ofglabellar rhytides (facial wrinkles). Further injections were given inmultiple locations along the hairlines, she also suffered from insomniawith difficulty initiating sleep and sustaining sleep. After injectionwith botulinum toxin, sleep pattern improved and lasted the duration ofabout 10-12 weeks. Total dose administered in multiple locations was 30Units.

Example 13

A 71 year old man with essential blepharospasm was injected with 60 Udivided along the peri-ocular region and the forehead. Improvement insleep pattern characterized by more continuous sleep was noted aftereach injection. The benefit lasted about 3 months and has been notedover 3 injection cycles. When brought to the patient's attention, heassociated the improvement to the botulinum toxin injections. Insomniarecurred when he felt the time for repeat injection with botulinumtoxin.

Example 14

A botulinum toxin composition is prepared from any immunotype (A-G)consisting of monocomponent neurotoxin molecules free of accessory orcomplex proteins, containing human serum albumin, and a nanoemulsion,with various charges. The nanoemulsion may contain polymers consistingof any of the following: polyethylene glycol, vegetable oil, a vegetableoil derivative or a monounsaturated or polyunsaturated oil. The pH maybe altered in the preparation to enhance permeability. Alternatively,botulinum toxin is prepared from immunotypes A-G consisting of amonocomponent neurotoxin, without a nanoemulsion carrier; albumin and anacidic pH between 1-6 units. The effect on the central nervous systemfrom transcutaneous injection was demonstrated using a rodent animalmodel typically used for research in neurodegenerative disease (20-30gram mice). Injections were given over the scalp region with botulinumtype A toxin at a dose close and approximating the LD₅₀ for this animal.Surviving animals were subjected to autopsy and serial brain cutting andhistologically stained using a standard Nissle formula. Substantialatrophy of basal ganglion and periventriclular cells was noted. Suchchanges are not usually seen with systemic illness without direct brainpathology. The neuropathologic assessment is that direct suppressanteffects do occur within the central nervous system at high dose (closeto the LD₅₀ for the animal model). More subtle changes are anticipatedand seen at lower therapeutic doses based on clinical observations ofefficacy for insomnia, dysmenorrhea, depression and anxiety. Theexperimentation described herein indicates blockage of neurotransmissionusually of excitatory neurotransmitters to the extent that pathologicchange occurs in brain structures. The major central nervous systemneuroransmitters blocked include glutamate, norepinephrine,acetylcholine. GABA effects are augmented. SNAP-25 is noted to becleaved throughout the targeted areas.

Example 15

The effect on the central nervous system from transcutaneous injectionwas demonstrated using a rodent animal model typically used for researchin neurodegenerative disease (20-30 gram mice). Four injections ofbotulinum toxin (totaling 0.8 LD₅₀ units) were given over the scalpregion. Surviving animals were subjected to autopsy and serial braincutting and histologically stained using a standard Nissle formula.Substantial atrophy of basal ganglion and periventriclular cells wasnoted. Substantial decrease of cholinergic neurons was noted.Substantial decrease in the amount of choline acetyltransferase wasnoted. More subtle changes are anticipated at lower therapeutic dosesbased on clinical observations of efficacy for insomnia, dysmenorrhea,depression and anxiety. The experimentation described hereindemonstrates blockage of neurotransmission usually of excitatoryneurotransmitters to the extent that pathologic change occurs in brainstructures. The major central nervous system neuroransmitters blockedinclude glutamate, norepinephrine, and acetylcholine. GABA effects areaugmented. SNAP-25 is noted to be cleaved throughout the targeted areas.

Example 16

The effect on the central nervous system from transcutaneous injectionwas demonstrated using a rodent animal model typically used for researchin neurodegenerative disease (20-30 gram mice). Four injections ofbotulinum toxin (totaling 0.8 LD₅₀ units) were given over the scalpregion. Surviving animals were subjected to autopsy and serial braincutting and histologically stained using a standard Nissle formula.Serial cut mouse tissue sections were stained for Nissle substance usingcresyl violet and immunostained for glutamate receptor activity.Sections were rinsed in TRIS-buffered saline with Tween 20 (TBS-T)containing 10% normal goat serum for one hour. Sections were thenincubated overnight in TBS-T with 0.1% sodium azide and anti-GluR4.Sections were rinsed three times in TBS-T, followed by a 2-3 hourincubation in TBS-T containing a goat anti-mouse peroxidase-conjugatedsecondary antibody to detect glutamate. Sections were then rinsed threetimes in TBS-T. Antibod y complexes were visualized usingdiaminobenzidine. Preabsorbtion with excess target protein, or omissionof either primary or secondary antibody, were used to demonstrateantibody specificity and background generated from the detection assay.Tissue sections were examined using a Nikon Eclipse E800 microscope witha Spot RT digital camera. Photographs of tissue sections of neostriatumin an untreated mouse (sham injection) and a botulinum toxin treatedmouse (four injections totaling 0.8 LD₅₀ BOTOX® injected transdermallyover the scalp reason) shown in FIG. 1.

1. A method of treating depression comprising the steps of a)identifying a subject with a depressive disorder or identifying asubject with one or more symptoms of a depressive disorder; and b)administering an effective amount of a composition comprising abotulinum toxin and a pharmaceutically acceptable carrier to saidsubject thereby reducing at least one symptom of depression. 2.(canceled)
 3. The method of claim 1, wherein the botulinum toxin isbotulinum toxin type A from Hall strain Clostridium botulinum. 4.(canceled)
 5. The method of claim 1, wherein administration is byinjection and there are at least two injection sites.
 6. The method ofclaim 1, wherein administration is by injection and the injection ismultifocal.
 7. The method of claim 5, wherein the composition isadministered to the forehead.
 8. The method of claim 7, wherein thecomposition is administered to the scalp.
 9. The method of claim 7,wherein the composition is administered to the neck.
 10. The method ofclaim 1, wherein said administration of said botulinum toxin blocks atleast one neurotransmitter and wherein said at least oneneurotransmitter is at least one of acetylcholine, glutamate, andnorepinephrine.
 11. (canceled)
 12. A method of treating depressioncomprising administering a therapeutically effective amount of abotulinum toxin subdermally, non-intramuscularly to a face of a subjectwith depression, thereby treating the depression by reducing theoccurrence of a symptom of the depression.
 13. The method of claim 12,wherein the step of administering further comprises administering thebotulinum toxin to a periocular region of the face.
 14. (canceled) 15.The method of claim 12, wherein the step of administering furthercomprises administering the botulinum toxin to locations that maximizeuptake by a portal hypophyseal drainage.
 16. (canceled)
 17. The methodof claim 12, wherein the botulinum toxin is administered subdermally.18. The method of claim 12, wherein the botulinum toxin is administerednon-intramuscularly.
 19. (canceled)
 20. (canceled)
 21. The method ofclaim 12, wherein the step of administering further comprises locallyadministering a therapeutically effective amount of the botulinum toxinsubdermally, non-intramuscularly to the face of a patient withdepression.
 22. The method of claim 12, wherein the symptom ofdepression further comprises at least one of the group consisting of:depressed mood; markedly diminished interest or pleasure in activities;significant weight loss or gain; insomnia or hypersomnia; psychomotoragitation, anxiety, or retardation; fatigue or energy loss; feelings ofguilt and worthlessness; impaired concentration and indecisiveness; andrecurring thoughts of death or suicide.
 23. (canceled)
 24. (canceled)25. The method of claim 22, wherein the botulinum toxin is administeredsubdermally, non-intramuscularly.
 27. (canceled)
 28. (canceled)
 29. Themethod of claim 22, wherein the step of administering further compriseslocally administering a therapeutically effective amount of thebotulinum toxin subdermally, non-intramuscularly to the face of apatient with depression.
 30. The method of claim 12, wherein thedepression further comprises one of the group consisting of: majordepression; dysthymia; minor depression; seasonal affective disorder;and atypical depression.
 31. A method for treating a neurologicaldisorder selected from the group consisting of seizure disorders,chronic surgical wound pain, pain syndrome, myofascial pain, muscletension headache, or trigeminal neuralgia, comprising the step oflocally administering a botulinum toxin to at least one of a scalp,face, or neck of a patient with the neurological disorder, therebytreating the neurological disorder by reducing the occurrence of asymptom of the neurological disorder. 32.-39. (canceled)